Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof

Abstract

Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including inflammatory and immune diseases, obesity and diabetes having the structure of formula (I), its enantiomers, diastereomers, or a pharmaceutically acceptable salt, or hydrate, thereof, wherein X is (Ia); or X is (Ib); or X is (Ic); (Id) is heterocycle or heteroaryl; E is —N—, —NR 1 —, —O—, —S—, —SO 2 — or —CR 2 —; F is —N—, —NR 1a —, —O—, —S—, —SO 2 — or —CR 2a —; G is N, —NR 1b —, —O—, —S—, —SO 2 — or —CR 2b —, provided that the E-F-G containing heterocyclic ring formed does not contain a S—S or S—O bond, and at least one of E, F and G is a heteroatom; J, J a , M, M a , Q, R x , R y , R 1 , R 1a , R 1b , R 2 , R 2a , R 2b , and R 3 to R 21 , Z, Z a , Z b , and Z c are as defined above.

1. A compound according to formula I, 
       
         
           
           
               
               
           
         
         its enantiomers, diastereomers, tautomers, or a pharmaceutically-acceptable salt thereof, wherein the side chain group 
       
       
         
           
           
               
               
           
         
         is attached to the bicyclic ring 
       
       
         
           
           
               
               
           
         
          at the 5- or 6-position;
 X is 
 
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
            is heterocyclo or heteroaryl; 
           E is —CR 2 —; 
           F is —N—; 
           G is —NR 1b —; 
           J is C; 
           J a  is C; 
           M-M a  is alkyl, haloalkyl, aryl, cycloalkyl, alkenyl, arylalkyl, heteroaryl, heterocyclo, alkylarylalkyl, alkylaryl, or haloaryl; 
           Q is selected from
 (i) hydrogen or C 1 -C 4  alkyl; 
 (ii) Q and R 6  are combined with the carbons to which they are attached to form a 3- to 6-membered cycloalkyl; or 
 (iii) Q and -M a -M are combined with the carbons to which they are attached to form a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms which are the same or different and are independently selected from the group consisting of O, S, SO 2 , and 
 
         
       
       
         
           
           
               
               
           
         
         
           which ring may be optionally substituted with 0-2 R 3  groups or carbonyl; 
           Z is selected from H, alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, —C(═O)C(═O)R 22 , —C(═O)NR 8 R 9 , —C(═O)R 8 , —C(NCN)NR 8 R 9 , —C(═O)OR 8 , —SO 2 R 8 , 
         
       
       
         
           
           
               
               
           
         
         
            and —SO 2 NR 8 R 9 ; 
           Z a  is a linker between N and Z and is selected from a bond; C 1 -C 5  alkylene; C 1 -C 5  alkylene which includes at any position in the chain a nitrogen which is substituted with alkyl, or an SO 2  group; —C(R z     1   )(R z     2   )C(═O)N(R z     3   )—; and —C(R z     1   )(R z     2   )S(═O) 2 N(R z     3   )- (where R z     1    and R z     2    at each occurrence are independently selected from H, C 1 -C 4  alkyl and halogen, and R z     3    is H or C 1 -C 4  alkyl); 
         
       
       
         
           
           
               
               
           
         
         (wherein for each C in the chain 
       
       
         
           
           
               
               
           
         
          R z     1    and R z     2    are independently H, C 1 -C 4  alkyl or halogen, and the right side of each Z a  group is linked to Z);
 R x  and R y  are the same or different and at each occurrence are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; 
 R 1b  is aryl; 
 R 2  is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR 10 , —NR 10 R 11 , —C(═O)R 10 , —CO 2 R 10 , —C(═O)NR 10 R 11 , —O—C(═O)R 10 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , —NR 10 C(S)OR 11 , —S(═O) p R 12 , —NR 10 SO 2 R 12 , —SO 2 NR 10 R 11 , cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; 
 R 3  at each occurrence is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR 13 , —NR 13 R 14 , —C(═O)R 13 , —CO 2 R 13 , —C(═O)NR 13 R 14 , —O—C(═O)R 13 , —NR 13 C(═O)R 14 , —NR 13 C(═O)OR 14 , —NR 13 C(S)OR 14 , —S(═O) p R 15 , —NR 13 SO 2 R 15 , —SO 2 NR 13 R 14 , cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; 
 R 4  is selected from hydrogen, alkyl, halogen, and C 1 -C 4  alkoxy; 
 R 6  is selected from hydrogen or alkyl; 
 R 7  is selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl; 
 or R 6  and R 7  are taken together with the carbon to which they are attached to form a cycloalkyl group; 
 R 5 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 16 , R 17 , R 19  and R 20  are the same or different and at each occurrence are independently selected from
 (i) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, carboxy, alkoxycarbonyl, and heterocyclo; or 
 (ii) with respect to Z, R 8  is taken together with R 9 ; and/or with respect to R 3 , R 13  is taken together with R 14 ; and/or with respect to R 6 , R 16  is taken together with R 17 ; and/or with respect to R 7 , R 19  is taken together with R 20 , each of which forms a 4- to 6-membered heteroaryl, and heterocyclo ring; 
 
 R 12 , R 15 , R 18 , and R 21  are the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; and 
 R 22  is selected from alkyl and alkoxy; 
 p is 0, 1 or 2; 
 provided that 
 1) R 2  cannot be NH 2 ; or 
 2) —Z a —Z is other than H; or 
 3) when Q and R 6  are combined with the carbons to which they are attached to form a 3- to 6-membered cycloalkyl, —Z a —Z cannot be alkyl; or 
 4) Z a —Z cannot be a substituted or unsubstituted 4-piperidinyl group; or 
 5) R 2  is other than —C(═O)CH 2 NO 2 ; or 
 6) when Q and M-M a  (and the carbon to which they are attached) combine to form a 5- or 6-membered ring, then —Z a —Z cannot be H or C 1 -C 5  alkyl or —C(═O)C(═O)NH 2 ; or 
 7) when Q and R 6  (and the carbons to which they are attached) combine to form a substituted or unsubstituted 3- to 6-membered carbocyclic ring, neither Z a  nor Z can be H or alkyl; or 
 8) where —Z a —Z is alkyl, then
 a) at least one of Q, R 6 , R 7 , R x  and R y  is other than H or alkyl, or M a -M is other than alkyl, or 
 b) Q is other than H, or 
 c) R 6  and R 7  are each other than H, or 
 d) R x  and R y  are each other than H; or 
 
 9) where R 2  is H, then: 
 a) when -M a -M is alkyl and —Z a —Z is 
 
       
       
         
           
           
               
               
           
         
         
            then —NR 8 R 9  or 
         
       
       
         
           
           
               
               
           
         
         
            is other than 
         
       
       
         
           
           
               
               
           
         
         
            wherein the term “alkyl” by itself or as part of another group refers to unsubstituted straight chain or branched chain alkyl; or 
           b) when —Z a —Z is —SO 2 R 8  or —SO 2 C(R z     1   )(R z     2   )H, then -M a -M is other than C 1 -C 4  alkyl or —C(R m     1   )(R m     2   )C(═O)N(R m     3   )H; or 
           c) where Q is H or C 1 -C 5  alkyl or C 1 -C 5  haloalkyl and/or M a -M is C 1 -C 5  alkyl or C 1 -C 5  haloalkyl, and R 6  and R 7  are independently H, C 1 -C 5  alkyl or C 1 -C 5  haloalkyl, and R x  and R y  are independently H, C 1 -C 5  alkyl or C 1 -C 5  haloalkyl, and Z a —Z is SO 2 R 8 , then R 8  is other than aryl or heteroaryl; or 
           d) when -M a -M is alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, then —Z a —Z cannot be unsubstituted straight chain alkyl or unsubstituted branched chain alkyl, —SO 2 — alkyl where alkyl is unsubstituted straight chain alkyl or unsubstituted branched chain alkyl, —SO 2 H, —SO 2 N(alkyl)(alkyl) where both alkyls are independently unsubstituted straight chain alkyl or unsubstituted branched chain alkyl, —SO 2 NH— alkyl where alkyl is unsubstituted straight chain alkyl or unsubstituted branched chain alkyl, —C(═O) alkyl where alkyl is unsubstituted straight chain alkyl or unsubstituted branched chain alkyl, —SO 2 NH 2 , —C(═O)N(alkyl)(alkyl) where both alkyls are independently unsubstituted straight chain alkyl or unsubstituted branched chain alkyl, —C(═O)NH alkyl where alkyl is unsubstituted straight chain alkyl or unsubstituted branched chain alkyl or —C(═O)NH 2 ; or 
           e) when -M a -M is aryl or alkyl, then where —Z a —Z is —SO 2 -alkyl or —C(═O) alkyl, then the alkyl portion of the —Z a —Z group is substituted straight chain alkyl or substituted branched chain alkyl where the substituent is other than alkyl. 
         
       
     
     
       2. The compound as defined in  claim 1  wherein the ring system 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound as defined in  claim 1  wherein
 R x  is H, unsubstituted alkyl or haloalkyl; 
 R y  is H, unsubstituted alkyl or haloalkyl; 
 M-M a - is unsubstituted alkyl, haloalkyl, aryl, cycloalkyl, alkenyl, arylalkyl, or heteroaryl; 
 Q is H or C 1 -C 4  alkyl; or 
 Q and M-M a  and the carbons to which they are attached can combine to form a -3- to 7-membered ring containing 1 or 2 heteroatoms, or a C 3 -C 7  cycloalkyl, or 
 Q and R6 and the carbons to which they are attached can combine to form a C 3 -C 6  cycloalkyl ring; 
 Z a  is a bond or C 1 -C 4  alkyl; and 
 Z is H, amino, alkyl, unsubstituted alkylcarbonyl, haloalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkoxycarbonylcarbonyl, carboxycarbonyl, heteroaryl, substituted heteroaryl, cycloalkyl, hydroxycycloalkyl, aminocycloalkyl, alkylcarbonylaminocycloalkyl, haloalkylsulfonyl, alkylaminocarbonyl, cyanoalkylcarbonyl, arylcarbonyl, alkylsulfonyl, alkoxyalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfonylalkylcarbonyl, arylalkylcarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl (or cycloheteroalkylalkylcarbonyl), alkylcarbonylaminoalkylcarbonyl, alkoxyarylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, arylaminocarbonyl, alkoxycarbonyl, carboxyalkylcarbonyl, alkylcarbonylalkylcarbonyl, aminosulfonylalkylcarbonyl, hydroxyalkylcarbonyl, haloalkylcycloalkylcarbonyl, haloalkylalkylcarbonyl, cycloalkylsulfonyl, alkylsulfonylalkylsulfonyl, haloalkylarylsulfonyl, dialkylaminosulfonyl, heterocycloaminocarbonyl, alkynylaminocarbonyl, diarylalkylaminocarbonyl, alkylthioalkyl(alkoxycarbonyl)aminocarbonyl, alkylcycloalkylaminocarbonyl, arylalkylaminocarbonyl, (hydroxylaryl)(alkoxyalkyl)aminocarbonyl, alkyl(hydroxyalkyl)(aminocarbonyl)aminocarbonyl, hydroxyheterocycloaminocarbonyl, arylalkylheterocycloaminocarbonyl, (haloarylalkyl)(hydroxyalkyl)aminocarbonyl, haloalkylalkylaminocarbonyl, cycloalkylaminocarbonyl, haloalkylalkoxycarbonyl, hydroxyalkylaminocarbonyl, alkyl(alkyl)aminocarbonyl (where alkyls are the same or different), heterocycloalkylaminocarbonyl, 
 
       
         
           
           
               
               
           
         
          hydroxyalkylheterocyclocarbonyl, aminoheterocyclocarbonyl, aminoalkylamino, alkoxycarbonylalkylaminocarbonyl, hydroxyalkylcycloalkylaminocarbonyl, alkylaminosulfonyl, alkylheterocyclo, dihydroxyalkyl(alkyl)aminocarbonyl, (hydroxyl)alkyl, carboxyalkylaminocarbonyl, cyanoheterocycloaminocarbonyl, heterocyclocarbonylalkylaminocarbonyl, haloarylalkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylcarbonyl, arylaminocarbonylalkylaminocarbonyl, haloarylalkylcarbonyl, alkyl(hydroxyl)alkylcarbonyl, alkenylheterocycloaminocarbonyl, or hydroxyalkyl(alkyl)aminoalkylaminocarbonyl. 
       
     
     
       4. The compound as defined in  claim 1  wherein
 R 1b  is substituted aryl which is haloalkylaryl, haloaryl, haloalkylalkyl(halo)aryl, alkoxyaryl, hydroxyaryl, alkoxycarbonylaryl, carboxyaryl, or alkoxycarbonylaryl; 
 Z is selected from unsubstituted heteroaryl, alkoxycarbonylheteroaryl, alkylheteroaryl, cycloalkyl, aminoheteroaryl, cyanoheteroaryl, cycloalkylheteroaryl, hydroxyheteroaryl, alkylthioheteroaryl, dialkylheteroaryl, haloalkylheteroaryl, haloheteroaryl, hydroxycycloalkyl, aminocycloalkyl, alkylcarbonylaminocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, alkyl, and haloalkylcarbonyl; or 
 Z is substituted heteroaryl which is substituted with one, two or three groups which are the same or different and are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano, OR 1   c , NR 1   a R 1   b , C(═O)R 1   c , CO 2 R 1   c , C(═O)NR 1   a R 1   b , —O—C(═O)R 1   c , NR 1   a C(═O)R 1   b , NR 1   a C(═O)OR 1   b , NR 1   a C(═S)OR 1   b , S(O) p     1   R 1   c , NR 1   a SO 2 R 1   b , SO 2 NR 1   a R 1   b , cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl; 
 R 1   a , R 1   b , and R 1   c , are the same or different and are independently selected from (i) hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible R 1   a  is taken together with R 1   b  to form a heteroaryl or heterocyclo ring; 
 p 1  is 0, 1 or 2; 
 Z a  is a bond, C 1 -0 5  alkylene; 
 
       
         
           
           
               
               
           
         
         M-M a  is alkyl, aryl, cycloalkyl, heteroaryl, arylalkyl, heterocyclo, alkylarylalkyl, alkylaryl, or haloaryl; 
         Q is H or C 1 -C 4  alkyl, or 
         Q and R6 and the carbons to which they are attached can be combined to form 
       
       
         
           
           
               
               
           
         
         Q and M-M a  and the carbons to which they are attached can be combined to form 
       
       
         
           
           
               
               
           
         
       
     
     
       5. A compound as defined in  claim 1 , wherein
 E is CH, 
 R 1b  is 
 
       
         
           
           
               
               
           
         
         R 6  is H or CH 3 ; 
         R 7  is H, CH 3 , C 2 H 5 , C 3 H 7 , C 6 H 5 , Δ, i-C 3 H 7 , or —CH 2 —CH═CH 2 ; 
         or R 6  and R 7  together form 
       
       
         
           
           
               
               
           
         
         R 4  is H; 
         R x  is H, CH 3  or CF 3 ; 
         R y  is H, CH 3  or CF 3 ; 
         M-M a  is 
       
       
         
           
           
               
               
           
         
         and Q is H or CH 3 ; 
         or Q and M-M a  and the carbons to which they are attached are taken together to form 
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound as defined in  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       7. A compound having the structure 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       8. A pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier therefor. 
     
     
       9. A pharmaceutical combination comprising a compound as defined in  claim 1  and an immunosuppressant, an anticancer agent, an anti-viral agent, an anti-inflammatory agent, an anti-fungal agent, an anti-biotic, an anti-vascular hyperproliferation agent, an anti-depressant agent, a lipid-lowering agent, a lipid modulating agent, an antidiabetic agent, an anti-obesity agent, an antihypertensive agent, a platelet aggregation inhibitor, and/or an antiosteoporosis agent, wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or a meglitinide, wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor agonist, an aP2 inhibitor and/or an anorectic agent, wherein the lipid-lowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor, and wherein the antihypertensive agent is an ACE inhibitor, angiotensin II receptor antagonist, NEP/ACE inhibitor, calcium channel blocker and/or β-adrenergic blocker.